Pediatric Mood Disorders: From Neurobiology to Clinical Practice

Pediatric Mood Disorders:
From Neurobiology to Clinical
Fadi Maalouf, M.D.
Assistant Professor of Psychiatry
Child and Adolescent Psychiatry / AUBMC
Adjunct Asst Prof of Psychiatry
University of Pittsburgh
• Introduction
• Pediatric Depression
o Clinical Presentations and Epidemiology
o Etiology (genetics and neurobiology)
o Treatment
• Pediatric Bipolar Disorder
• Conclusion
Mood Disorders
• Unipolar disorders:
Major depressive disorder (Pediatric Depression)
Dysthymic disorder
Depressive disorder not otherwise specified (nos)
• Bipolar disorders:
Bipolar Type I, II, nos
Cyclothymic disorder
• Mood disorders secondary to a general medical
condition or substances..
Pediatric Depression
• Doubted the existence of pediatric
depression until mid 1970’s– immature
personality structures.
• In 1970 4th congress of European child
psychiatrist- Depressive states in children
and adolescents”.
• DSM III early 80’s criteria adjustment for
• Omar is a 13 year-old boy who presents to his
pediatrician with a few-month-history of recurrent
asthma attacks resulting from non-compliance with his
Upon further questioning,
• He has been failing his tests which is unusual for him.
• In addition, he has not been spending as much time
with friends
• He dropped out of basketball practice and has not been
going to family events.
• His mother, who is being treated for a “nervous
breakdown” reports that Omar has been quite irritable
• He has had difficulty getting up in the morning, and
appears tired.
• She reports that she found “dark poems” written in his
MDD in children and adolescents is characterized by one or more major depressive
episode, defined as at least 2 weeks of persistent change in mood manifested by
either depressed or irritable mood (in children) or loss of interest or pleasure
AND at least 4 additional symptoms of depression,
Changes in appetite or weight (or failure to achieve expected weight gain in
• Changes in sleep
• Psychomotor activity,
• Decreased energy,
• Feelings of worthlessness or guilt,
• Difficulty thinking or concentrating,
• Recurrent thoughts of death or suicidal ideation, plans, or attempts.
• The symptoms must persist for most of the day nearly every day, and must be
associated with an impairment in functioning (social, academic or other), must not
represent the direct physiologic effect of a substance or a general medical condition
and must not be better accounted for by bereavement.
Clinical Presentation
• Preschoolers may exhibit irritability, withdrawal, temper tantrums
or regression as symptoms of depression.
School-age children may display crying spells, or somatic
complaints such as headaches and stomachaches. They look sad
and describe themselves in a negative manner
“ I am dumb”, “ I am stupid”,
“ nobody likes me”.
School performance deteriorate.
• Adolescents: Irritability, loss of interest, substance use, suicidal
thoughts, hypersomnia.
Probability of Experiencing an Episode of Major Depressive Disorder as a
Function of Age and Gender
(Lewisnshon et. al 1998)
Social Developmental Changes in adolescence as risk
• Decreased adult supervision and support
• Increased concern about social status and social
• Increased parent-child conflict.
• Lifestyle changes that can predispose to depression,
such as substance use and sleep deprivation
(Dahl, 2004; Nelson et al., 2005)
Health risk behaviors
Tobacco and substance abuse
Overeating and obesity
Low physical activity
Engagement in unprotected sex and
Antisocial behavior
Brooks et al., 2002
It is recurrent: 40% experiencing a second
episode within 2 years, and nearly 75% within 5
years. Almost all will go on to experience
another episode in their adult life.
Age-Specific Rates of Major Depressive Disorder Over 20 Years in Offspring of
Depressed and Nondepressed Parents
( Weissman American Journal of Psychiatry 2006)
The percentage of individuals meeting diagnostic criteria for depression at age 26, as a function of 5HT T genotype and number of stressful life events between the ages of 21 and 26. The figure shows
individuals with either one or two copies of the short allele (left) and individuals homozygous for the
long allele (right). (Caspi et. al Science 2003)
Results of regression analysis estimating the association between childhood
maltreatment (between the ages of 3 and 11 years) and adult depression (ages 18 to 26),
as a function of 5-HT T genotype. (Caspi et. al Science 2003)
Genotype-based parametric comparisons illustrating significantly greater activity in the right amygdala
of the s group versus the l group
(A Hariri, Science 2002)
Neural model of emotion regulation illustrating neural systems implicated in voluntary and automatic subprocesses of
emotion regulation, (a) Feedforward pathway: medial prefrontal cortical system, including the OFC, subgenual ACG,
rostral ACG, hippocampus and parahippocampus and MdPFC. (b) Feedback pathway: lateral prefrontal cortical
system, including DLPFC and VLPFC. DLPFC, dorsolateral prefrontal cortex; MdPFC, dorsomedial prefrontal cortex;
ACG, anterior cingulate gyrus; VLPFC, ventrolateral prefrontal cortex; OFC, orbital frontal cortex; hipp/parahip,
hippocampus-parahippocampus region.
Why these domains
Phillips, M et. al 2003
“CANTABeclipse can be used with your own desktop, laptop or tablet PC
running Windows XP or 2000. Also available is the system pre-installed and
ready for use, on high specification tablet PCs with built-in touch screen”.
Subjects tested require no computer skills, interacting directly with the touch
screen and, for accurate reaction times, the supplied press pad.
Stockings of Cambridge
The subject must use the
balls in the lower display
to copy the pattern shown
in the upper one.
The balls may be moved
one at a time by touching
the required ball then
touching the position to
which it should be moved.
Forward Planning
• Maalouf et. al under review
Affective Go/ No-Go
The Affective Go/No-go (AGN)
test assesses information
processing biases and
inhibitory control for positive
and negative stimuli.
A series of words is rapidly
presented in the centre of the
screen. These words are
positive, negative or neutral
The subject is given a target
valence and is asked to press
the press pad when they see a
word that matches this
Affective Go/No-Go
Three dependent
measures of interest:
Response time (time to
respond to each target),
error rate (response to
distractor stimuli) and
omissions (failure to
respond to target).
Affective Bias
Maalouf et. al, 2009
• Why is it important to treat?
It is associated with substantial
impairment in school and
interpersonal relationships, tobacco
and substance abuse, suicide
attempts, and a 30-fold increased risk
of completed suicide.
• Clinical guidelines for the acute
management of adolescent depression
recommend the prescribing of selective
serotonin reuptake inhibitor (SSRI)
medications, with or without
psychotherapy, with the best-studied
psychotherapy being cognitive behavioral
therapy (CBT).
Weiz et. al 2006, Birmaher et al 2007
Mechanism of Action
• SSRI antidepressants work by inhibiting
reuptake of serotonin by pre-synaptic neurons,
with at least 70% reuptake inhibition required to
result in clinical improvement.
• Studies in adults show that antidepressants
increase dorsal prefrontal activity and decrease
limbic activity, which allows the patient to better
modulate emotional reactions.
Axelson et al., 2005 and Lesch et al., 1993.
They include
• Fluoxetine (Prozac) – FDA apporved (age
• Sertraline (Zoloft)
• Paroxetine ( Seroxat, Paxil CR)
• Fluvoxamine (Faverin),
• Citalopram (Cipram),
• and Escitalopram (Cipralex)- FDA
Treatment of Adolescent
Depression Study
• 439 adolescent outpatients with major
• Randomized to twelve weeks
Fluoxetine (10-40 mg/day)
CBT with fluoxetine (10-40 mg/day)
CBT alone
(Treatment for Adolescents with Depression Study Team (TADS),
JAMA, 2004; 292: 807-820)
TADS Response Rate
(Differed from
(Differed from
(Did not Differ
from PLB)
Positive Double-blind Placebo
Controlled Depression Trials
Number of studies
Negative Double-blind Placebo
Controlled Depression Trials
Number of studies
SSRI-side effects
Mood switching
Misc: Agitation, insomnia, nausea, initial
weight loss, decreased libido, irritability.
• Others-rare but serious (Serotonin
syndrome, EPS, elevated bleeding time)
Antidepressants and Suicide
By Marilyn Elias,
Could antidepressants prescribed for
more than 1 million U.S. children and
teenagers cause some of them to
attempt suicide?
• But what is the true story and how
did everything start?
• On Oct 15th 2004, a black box warning was
issued. “Antidepressants increase the risk
of suicidal thinking and behavior
(suicidality) in children and adolescents
with major depressive disorder (MDD) and
other psychiatric disorders”.
Suicidal Story-Ctn’d
• FDA pooled data from 24 studies that
examined SSRI use in a total of 4400
children/teenagers with MDD and/or
• The FDA performed post-hoc analyses
employing many sub-analyses since none
of the original 24 studies were designed to
study the impact of SSRI on suicidality.
Suicidal story-Ctn’d
• Which means a panel
of expert tried to best
determine whether an
event recorded years
ago may have
reflected suicidality.
What did the numbers show?
• 78 events of suicidal
thinking/behavior identified
among 4400 patients.
Efficacy vs suicide Risk of
Antidepressants in Pediatric Patients
But wait a minute
. Annual Rates of Depression in the Pediatric General
Medical and Specialty Managed Care Enrollee Population,
(libby et al , AJP, 2007
Suicide Rate in Children and Adolescents (Ages 5–19 Years) in
the United States, 1988–2004 (Gibbons et. al AJP 2007)
Clinical Course: Risk of Bipolar
• 20%-40% MDD youth develop bipolar disorder in 5
years of onset of MDD.
Predictors of Bipolar I Disorder Onset:
Early onset MDD
Psychomotor retardation
Family history of psychotic depression
Pharmacologically induced hypomania
What is Bipolar Disorder ?
• Costly, common (1%+), treatable
• Defined by recurrent episodes of mania (or
hypomania) and depression
• Often misdiagnosed
The DSM-IV categorizes it into:
• Bipolar I Disorder
• Bipolar II Disorder
• Cyclothymia
• Bipolar N.O.S.
Criteria for mania
• A. A distinct period of abnormally and persistently
elevated , expansive or irritable mood (class clown,
giddy, goofy)
• B. At least 3/7 (4/7 if mood is irritable)
1- D Distractibility
2- I
Increased Activity/ psychomotor agitation
3- G Grandiose or elevated self-esteem (bossy, defiant)
4- F Flight of ideas or racing thoughts
5- A Activities with painful consequences
6- S Sleep decreased
7- T Talkative or pressured speech
Parent Support group-Humor
You might have a child with bipolar disorder if ....
You spend more money on meds than on food
You have the psychiatrist on speed dial.
The school has YOU on speed dial!
You have holes in your walls and doors coming off the hinges, but that'
s the last thing
re worried about.
Everyone at the school knows your child, and gives you "the look".
All of your friends and family are ready, willing, and able to give YOU advice on what
to do with your child(ren), but refuse to even babysit for you for one night.
You drive like you'
re 100 years old for fear of an object being hurled at your head. .
re on a first name basis with your pharmacist.
Instead of passing condescending looks, you'
re sympathetic when you see a mom
with another child who is raging in public.
ve been kicked out of every daycare in town.
Some ways Pediatric Mood Disorders
differ from adult Mood Disorders
Children with Bipolar disorder have much faster and more frequent
cycles than adults .
• Children rarely have pure euphoric mania as defined by the DSM-IV.
They are more likely to have oppositional bossiness and irritability.
• The co-morbidity of other disorders can make medical treatment
very difficult in children. Children are more likely to be activated by
certain medications, namely antidepressants and psychostimulants,
than adults.
• Bipolar disorder in children is often misdiagnosed as unipolar
depression with hyperactivity. Treatment for unipolar depression is
vastly different from treatment for bipolar disorder .
Some ways Pediatric Mood Disorders are
similar to adult Mood Disorders
• Children can be suicidal. These ideations can quickly develop into
plans and actions.
• Children with mania have the same urges that adults do, they also
become hypersexual, grandiose, obsessive and desire to spend
• Children, like adults, require medication to stabilize their mood.
Therapy when coupled with medications has been quite successful.
• Stress, just as with adults, can trigger a relapse.
Towards mentally healthy
children--- Thanks